Ulf Dettmer

Ulf Dettmer

Assistant Professor of Neurology
Ulf Dettmer

My lab explores new strategies for the treatment of Parkinson's disease (PD) and related synucleinopathies such as Dementia with Lewy bodies (DLB), Multi-System Atrophy (MSA) and, to some extent, also Alzheimer's disease (AD). These diseases are characterized by the intracellular aggregation of the protein α-synuclein (αS), an abundant nerve cell component in the brain with a poorly defined function in synaptic vesicle maintenance. With no disease-modifying drugs available, there is a great need for robust models that recapitulate how early changes in the normal maintenance of α-synuclein can lead to these aggregates. We have published evidence that αS normally exists in a delicate equilibrium of membrane-associated vs. soluble and monomeric vs. multimeric species. Disturbance of this fine balance by genetic or environmental factors, we hypothesize, is an early key event in synucleinopathy pathogenesis. Protein engineering, where we introduce strategic point mutations into the normal αS sequence, has enabled us to model such disturbances and convert αS into an acutely toxic protein.

Combining cell biology, biochemistry, protein engineering, microscopy, high-content imaging and screening approaches, we want to continue in the lab to:

- better understand normal αS cell biology,
- define abnormal αS states,
- transform abnormal αS states into screenable phenotypes,
- use the correction of abnormal states as a readout for drug discovery in medium- and high-throughput screens.

Factors that we identify as promising to correct aberrant αS homeostasis will be tested in a novel DLB/PD mouse model that we designed and that is being characterized in depth in a collaboration.

Contact Information

Brigham and Women's Hospital
Building for Transformative Medicine, room 10002-M
60 Fenwood Road
Boston, MA 02115
p: 617-525-5761